Neuromyelitis optica

PURPOSE OF REVIEW: We review recent advances in neuromyelitis optica, an idiopathic inflammatory demyelinating disease of the central nervous system predominantly affecting optic nerves and spinal cord. We concentrate on a recently identified serum antibody biomarker, neuromyelitis optica immunoglobulin G (NMO-IgG), which distinguishes neuromyelitis optica from multiple sclerosis. RECENT FINDINGS: NMO-IgG is detected by indirect immunofluorescence. Its presence and specificity for neuromyelitis optica was confirmed in diverse populations. Seropositivity is now incorporated into new diagnostic criteria for neuromyelitis optica. Testing for this biomarker has suggested that the neuromyelitis optica spectrum is broader than previously recognized. Recently, the molecular target of NMO-IgG was identified as aquaporin-4. Immunopathologic studies suggest that loss of aquaporin-4 immunostaining is detectable in early lesions of neuromyelitis optica. A B-cell-specific monoclonal antibody, rituximab, may be an effective treatment even in patients not responding to other treatments. SUMMARY: Clinical, radiologic, and immunologic features distinguish neuromyelitis optica from other severe cases of multiple sclerosis. NMO-IgG is the first specific marker for a central nervous system demyelinating disease. The discovery of aquaporin-4 as the putative target of NMO-IgG, and recent data suggesting that aquaporin-4-specific antibodies are pathogenic may enhance our understanding of idiopathic inflammatory demyelinating diseases and their treatment.     

水通道蛋白4抗体检测对视神经脊髓炎的诊断价值

目的:探讨水通道蛋白4(AQP4)抗体检测对视神经脊髓炎(NMO)的诊断价值.方法:采用表达人AQP4基因的人胚肾(HEK)293细胞株分别对35例NMO患者(NMO组)、14例NMO高危综合征患者(HRS组)、37例多发性硬化患者(MS组)、23例其他脱髓鞘疾病患者(ODD组)及75例其他神经系统疾病患者(MD组)的血标本进行AQP4抗体检测,比较各组抗体的阳性率.结果:NMO组中31例患者(88.6%)及HRS组中6例患者(42.9%n)AQP4抗体检测为阳性;MS组、ODD组和MD组患者AQP4抗体检测均为阴性.NMO组AQP4抗体检测阳性的敏感性为88.6%,95%CI,73.11%-96.79%;HRS组AQP4抗体检测阳性的敏感性为42.9%,95%CI:16.97%-68.83%;NMO患者AQP4抗体检测阳性的特异性为100%.结论:AQP4抗体检测对NMO及其疾病谱早期确诊有重要意义,且具有较高的敏感性和特异性.     

Neuromyelitis optica spectrum disorders may be misdiagnosed as Wernicke's encephalopathy

Purpose: To raise doctors’ attention to the differential diagnosis of neuromyelitis optica spectrum disorders (NMOSD) and Wernicke's encephalopathy (WE). Patients and methods: We extensively reviewed the medical records of 136 patients who had visited our hospital since 2008 and were suspected of having central nervous system demyelinating diseases. Four of those patients had somnolence, electrolyte imbalance and brain lesions around the third ventricle and were included in the study. We tested the serum of the four patients for the presence of aquaporin-4 (AQP4) M23 antibody. Results: All the four patients had positive AQP4 antibody in their serum. Two of the patients were misdiagnosed as WE before AQP4 antibody detection occurred. Conclusions: NMOSD and WE have similar brain lesion locations, histopathological changes and clinical manifestations. It is important to distinguish NMOSD from WE by detecting AQP4 antibody in serum or cerebral spinal fluid. Vitamin B1 should also be administered to the patients who have a history of thiamine deficiency.     

水通道蛋白4与视神经脊髓炎

水通道蛋白4（AQP4）是具有高度选择性的水通道特异蛋白，参与脑脊液的重吸收和渗透压调节。目前研究发现AQP4还参与视神经脊髓炎（NMO）的体液免疫机制，揭示了NMO是一种自身免疫性通道病，这一发现使NMO的免疫和病理学研究进入了一个新的阶段。AQP4作为NMO自身免疫反应攻击的靶点，为NMO的诊断和治疗开启一个新的领域。     

2015年视神经脊髓炎谱系疾病诊断标准临床应用评估

目的 评估2015年视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorder,NMOSD)诊断标准的临床应用.方法 回顾性分析作者医院2008-3-2016-8收治的605例中枢神经系统脱髓鞘疾病患者临床资料,并分别采用2015年NMOSD诊断标准及2006年NMO诊断标准对其进行诊断分析.结果 共有176例患者符合2015年NMOSD诊断标准,其中108例(61.4％)符合2006年NMO诊断标准.AQP4-IgG阳性患者139例(79.0％).当假设该139例患者AQP4-IgG水平未知时,共有91例(65.5％)符合2015年NMOSD诊断标准,而仅有55例(39.6％)满足2006年NMO诊断标准(P＜0.05).176例患者中有39例同时满足2006年NMO诊断标准和201 5年NMOSD诊断标准且以临床孤立病灶起病,在疾病早期通过2006年NMO诊断标准尚不能与多发性硬化相鉴别,但已符合2015年NMOSD诊断标准.在核心症状方面,NMOSD患者中以急性脊髓炎(50.6％)和视神经炎(31.8％)起病者所占比例最高,其次为最后区综合征(5.7％).结论 2015年NMOSD诊断标准较2006诊断标准扩大了疾病的诊断范围,且在AQP4-IgG水平未知的情况下仍具有更高的诊断敏感性,对于疾病早期与多发性硬化的鉴别中具有重要作用,且更加强调了疾病的核心症状.     

Neuromyelitis optica - an update: 2007�C2009

Neuromyelitis optica is an inflammatory demyelinating disorder of the central nervous system. The discovery of a specific antibody (NMO IgG /aquaporin-4 antibody) in patients with this condition has led to a marked revival of research on the disease. This article summarizes the major advances in neuromyelitis optica, particularly in the last 2 years, and supplements the previous review published in this Journal in 2007. Important among these developments are: the epidemiological studies, which have provided estimates of incidence and prevalence; identification of mutations in the aquaporin-4 gene; improved understanding of the effects of anti-aquaporin-4 antibody on astrocytes; roles of excitatory amino acid transporter type 2 and glutamate; requirement of aquaporin-4 to be in orthogonal arrays to be antigenic; recognition of the presence of aquaporin-4 antibody in patients with cancer and posterior reversible encephalopathy syndrome; possibility of monitoring the disease using the antibody, and the effectiveness of rituximab and mycophenolate in preventing relapses.     

Aquaporin 4 and neuromyelitis optica

Neuromyelitis optica is an inflammatory demyelinating disorder of the CNS. The discovery of circulating IgG1 antibodies against the astrocyte water channel protein aquaporin 4 (AQP4) and the evidence that AQP4-IgG is involved in the development of neuromyelitis optica revolutionised our understanding of the disease. However, important unanswered questions remain--for example, we do not know the cause of AQP4-IgG-negative disease, how astrocyte damage causes demyelination, the role of T cells, why peripheral AQP4-expressing organs are undamaged, and how circulating AQP4-IgG enters neuromyelitis optica lesions. New drug candidates have emerged, such as aquaporumab (non-pathogenic antibody blocker of AQP4-IgG binding), sivelestat (neutrophil elastase inhibitor), and eculizumab (complement inhibitor). Despite rapid progress, randomised clinical trials to test new drugs will be challenging because of the small number of individuals with the disorder.     

Demyelinating Peripheral Neuropathy in Devic Disease

Abstract: This is a report of a 20-year-old man with typical features of Devic disease (neuromyelitis optica) associated with demyelinating peripheral neuropathy. A sural nerve biopsy showed markedly decreased myelinated fibers of a large diameter. Teased fiber preparations showed segmental remyelination in 50% of examined fibers, as well as a few demyelination. Demyelination of bilateral optic nerves, spinal cord, and peripheral nerves at the same time suggests a possibility of common pathogenetic mechanisms in both the central and peripheral nervous systems.     

Myopathy associated with neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders (NMOSD) were generally thought to affect only central nervous system and spare peripheral aquaporin-4 (AQP4)-expressing organs. In recent years, however, increasing evidence has shown that skeletal muscle is involved in NMOSD. We provided a comprehensive review of the relevant literature and summarized the clinical and pathological characteristics of myopathy associated with NMOSD. NMOSD-associated myopathy seems to be characterized by mild muscle symptoms with prominent hyperCKemia and minimal changes on conventional pathological staining. Loss of AQP4 and deposition of IgG and activated complement products on sarcolemma of type II fibers are diagnostic features on immunohistochemical examinations. Creatine kinase leakage as a result of AQP4-IgG-induced, complement-mediated sarcolemmal injury may be a potential mechanism for hyperCKemia. Myopathy should be considered a component of NMOSD unified by AQP4-IgG seropositivity.     

Aquaporin‐4 orthogonal arrays of particles are the target for neuromyelitis optica autoantibodies

Neuromyelitis optica (NMO) is an inflammatory autoimmune demyelinating disease of the central nervous system (CNS) which in autoantibodies produced by patients with NMO (NMO‐IgG) recognize a glial water channel protein, Aquaporin‐4 (AQP4) expressed as two major isoforms, M1‐ and M23‐AQP4, in which the plasma membrane form orthogonal arrays of particles (OAPs). AQP4‐M23 is the OAP‐forming isoform, whereas AQP4‐M1 alone is unable to form OAPs. The function of AQP4 organization into OAPs in normal physiology is unknown; however, alteration in OAP assemblies is reported for several CNS pathological states. In this study, we demonstrate that in the CNS, NMO‐IgG is able to pull down both M1‐ and M23‐AQP4 but experiments performed using cells selectively transfected with M1‐ or M23‐AQP4 and native tissues show NMO‐IgG epitope to be intrinsic in AQP4 assemblies into OAPs. Other OAP‐forming water‐channel proteins, such as the lens Aquaporin‐0 and the insect Aquaporin‐cic, were not recognized by NMO‐IgG, indicating an epitope characteristic of AQP4‐OAPs. Finally, water transport measurements show that NMO‐IgG treatment does not significantly affect AQP4 function. In conclusion, our results suggest for the first time that OAP assemblies are required for NMO‐IgG to recognize AQP4. © 2009 Wiley‐Liss, Inc.,     

Lesions of the posterior limb of the internal capsule in neuromyelitis optica spectrum disorder

Posterior limb of the internal capsule lesions (PLICL) are one of the MRI features of neuromyelitis optica spectrum disorder (NMOSD). However, there is no evidence that such lesions are pathogenically related to NMOSD. We retrospectively analyzed features of PLICL in NMOSD, and other central nervous system inflammatory disorders, in 561 patients. We also examined the pathological samples of six patients. Of the 561 patients investigated, PLICL were found in 65 patients (11.6%). Lesions were bilateral in 26 cases (40%) and unilateral in 39 cases (60%). Unilateral lesions were mainly located on the left side (74.3%, 29/39). Of the 65 patients with PLICL, 46 patients had NMOSD (70.8%) and were positive for anti-aquaporin (AQP4-IgG), four had NMOSD (6.2%) and were AQP4-IgG negative, 10 patients had multiple sclerosis (MS), three patients had NMDAR encephalitis, and two had autoimmune meningoencephalitis. Of the six patients whose pathological samples were evaluated, all had PLICL and were negative for AQP4-IgG, and none had pathological NMOSD lesion features. These cases included three patients with multiple sclerosis, one with anti-N-methyl-D-aspartate receptor encephalitis, and two with autoimmune meningoencephalitis. In conclusion, PLICL are found not only in patients with NMOSD, but also in MS and other disorders.     

Neuromyelitis optica with intraspinal expansion of Schwann cell remyelination

We report a case of neuromyelitis optica (NMO) with an unusual pattern of remyelination in the spinal cord. A Japanese woman complained of pain and numbness in the left thumb at the age of 36 years. She mainly presented with optic and spinal symptoms and was initially diagnosed as multiple sclerosis (MS). Her bilateral eyesight decreased, which led to light perception only in the right eye. She became unable to walk without a wheelchair. In spite of steroid pulse therapy, plasma exchange therapy and immunosuppressive therapy, her symptoms gradually worsened. After 33 years of a relapsing–remitting course, she died of septic urinary tract infection at the age of 69 years. Autopsy revealed prominent demyelination in the optic tract and the spinal cord. The optic nerve showed extensive demyelination accompanied by axon depletion. The spinal cord lesions were found in C8 to L2 level (contiguous 15 segments), especially Th5 to Th11 level. The thoracic spinal cord showed extensive remyelination spreading from the entry zone of peripheral nerves to the central portion. Regenerative myelin showed immunopositivity for Schwann/2E, a marker of Schwann cells and myelin of the peripheral nervous system. Expressions of glial fibrillary acidic protein and aquaporin 4 (AQP4) were weakened in the area of Schwann cell remyelination, suggesting that the essential pathogenesis of this case was disturbance of astrocytes. Inhibition of gliosis probably led to cystic cavities, and destruction of basal lamina may have permitted Schwann cells of peripheral nerves to enter the spinal cord and proliferate within empty spaces. Compared with the optic tract and the spinal cord lesions, a large part of the brain plaques was vague and inactive. We pathologically diagnosed this case as NMO for optic neuritis, myelitis, a contiguous spinal cord lesion and loss or decrease of AQP4 expression.     

Devic's neuromyelitis optica: long-term follow-up and serial CSF findings in two cases

Summary Sixteen cerebrospinal fluid (CSF) specimens serially obtained during long-term follow-up of two patients with Devic's neuromyelitis optica (DNO) were compared with 65 CSF samples from patients with multiple sclerosis (MS). By statistical analysis, the CSF profile in DNO was found to differ from that observed in MS, mainly showing pleocytosis, blood-brain barrier damage, and absence of persistent immunoglobulin G synthesis within the central nervous system. Oligoclonal bands, detected with isoelectric focusing, were present in CSF of 92% of the patients with MS, and in three CSF specimens from one patient with DNO during the first 6 months after disease onset. The bands disappeared in two subsequent samples. This finding has never been described in MS. One patient with DNO had an apparent chronic-relapsing course probably due to steroid dependence. The clinical and CSF features of our cases favour the nosographic independence of DNO and MS.     

2015年视神经脊髓炎谱系疾病诊断标准国际共识解读

（aquaporin-4,AQP4）抗体的发现,加深了人们对 NMO 的认识,并扩展了 NMO 谱系疾sclerosis,MS）的一种中枢神经系统特发性炎性疾病。NMO 高度特异性的水通道蛋白4视神经脊髓炎（neuromyelitis optica,NMO）是不同于多发性硬化（multiple （International Panel for NMO Diagnosis,IPND）对 NMOSD 诊断标准进行了修订,并达病（neuromyelitis optica spectrum disorders,NMOSD）的定义。NMO 诊断国际专家组成2015年 NMOSD 诊断标准国际共识。该诊断标准取消了 NMO 的个别定义,而将 NMO归入 NMOSD。同时,根据 AQP4抗体表达状态,分为 AQP4抗体阳性和 AQP4抗体阴性NMOSD。AQP4抗体阳性 NMOSD 的诊断要求具备6项核心症状之一;AQP4抗体阴性或无法进行 AQP4抗体检测的 NMOSD 的诊断,要求则更为严格,必须有特征性的 MRI 表现。本文即对2015年 NMOSD 诊断标准国际共识中的要点进行解读和评论。     

Neuromyelitis optica spectrum disorders: Features of aquaporin-4, myelin oligodendrocyte glycoprotein and double-seronegative-mediated subtypes

The new diagnostic classification of neuromyelitis optica spectrum disorder (NMOSD) in 2015 highlights the central role of biomarkers, such as antibodies against aquaporin-4 (AQP4-Ab), in diagnosis. Also, in approximately 20–25% of patients without AQP4-Ab (NMOSD^AQP4?) the presence of an antibody directed against myelin oligodendrocyte glycoprotein (MOG) characterizes a specific population of NMOSD patients (NMOSD^MOG+), according to their demographic and clinical data and prognoses. While double-seronegative cases (NMOSD^NEG) have not been fully described, they may correspond to the very first patients with opticospinal demyelination reported by Devic and Gault in 1894. The present report reviews the current knowledge of the pathophysiology and clinical features of NMOSD^AQP4+, NMOSD^MOG+ and NMOSD^NEG patients, and also discusses the relationship between the extended spectrum of MOG disease and NMOSD^MOG+. Finally, the current treatments for acute relapses and relapse prevention are described, with a focus on serological-based therapeutic responses and the promising new therapeutic targets.     

Involvement of Aquaporin 4 in Astrocyte Function and Neuropsychiatric Disorders

Aquaporin 4 (AQP4) is the main water channel in the central nervous system (CNS) and specifically localized to astrocyte processes. Recent studies indicate that AQP4 regulates various biological functions of astrocytes, including maintaining CNS water balance, spatial buffering of extracellular potassium, calcium signal transduction, regulation of neurotransmission, synaptic plasticity, and adult neurogenesis, while under neuropathological conditions, AQP4 has a role in astrogliosis and proinflammatory cytokine secretion. In addition, accumulating evidence suggests that, besides cerebral edema, neuromyelitis optica and epilepsy, AQP4 participates in the onset and progression of Alzheimer disease, Parkinson disease, depression, and drug addiction. This review summarizes recent findings and highlights the involvement of AQP4 in astrocyte function and neuropsychiatric disorders.     

Higher frequency of brain abnormalities in neuromyelitis optica spectrum disorder patients without primary Sj?gren's syndrome

Neuromyelitis optica spectrum disorder otfen co-exists with primary Sj?gren’s syndrome. We compared the clinical features of 16 neuro-myelitis optica spectrum disorder patients with (n = 6) or without primary Sj?gren’s syndrome (n = 10). All patients underwent extensive clinical, laboratory, and MRI evaluations. hTere were no statistical differences in demographics or ifrst neurological involvement at onset between neuromyelitis optica spectrum disorder patients with and without primary Sj?gren’s syndrome. The laboratory findings of cerebrospinal lfuid oligoclonal banding, serum C-reactive protein, antinuclear autoantibody, anti-Sj?gren’s-syndrome-related antigen A an-tibodies, anti-Sj?gren’s-syndrome-related antigen B antibodies, and anti-Sm antibodies were signiifcantly higher in patients with primary Sj? gren’s syndrome than those without. Anti-aquaporin 4 antibodies were detectable in 67% (4/6) of patients with primary Sj?gren’s syndrome and in 60% (6/10) of patients without primary Sj?gren’s syndrome. More brain abnormalities were observed in patients without primary Sj?gren’s syndrome than in those with primary Sj?gren’s syndrome. Segments lesions (> 3 centrum) were noted in 50% (5/10) of patients without primary Sj?gren’s syndrome and in 67% (4/6) of patients with primary Sj?gren’s syndrome. hTese ifndings indicate that the clinical characteristics of neuromyelitis optica spectrum disorder patients with and without primary Sj?gren’s syndrome are similar. However, neu-romyelitis optica spectrum disorder patients without primary Sj?gren’s syndrome have a high frequency of brain abnormalities.     

Hypothalamic abnormality in patients with inflammatory demyelinating disorders

Background: Hypothalamic lesions in neuromyelitis optica (NMO) patients might be more specific for NMO than multiple sclerosis (MS). However, this is controversial. Objective: To characterize clinical features of patients with inflammatory demyelinating disorders (IDDs) with visible hypothalamic lesions using magnetic resonance imaging (MRI). Methods: Patients with IDDs (n = 429) were recruited retrospectively. Results: Of 52 patients with hypothalamic images enrolled, 42 were positive for aquaporin-4 (AQP4) antibodies, including 28 patients with NMO, 6 with recurrent transverse myelitis, 3 with recurrent optic neuritis, and 5 with brainstem and brain syndrome. The remaining 10 patients were anti-AQP4-negative, including 3 with MS, 3 with acute disseminated encephalomyelitis, and 4 with other disorders. In the AQP4-positive group, manifestations, including ataxia, intractable hiccup and nausea, syndrome of inappropriate antidiuretic hormone secretion and encephalopathy were more frequent in those with hypothalamic lesions than those without. Cell counts of cerebrospinal fluid in patients with hypothalamic lesions differed from patients without lesions. Brain MRI abnormalities were more frequent in brainstem and hemisphere of the hypothalamic lesion group. Conclusions: Hypothalamic lesions were observed frequently in patients with AQP4 antibodies. Clinical manifestations and paraclinical features in AQP4-positive patients with hypothalamic lesions differed from those without lesions.     

Neuromyelitis optica associated with myasthenia gravis: characteristic phenotype in Japanese population

We report two female patients with neuromyelitis optica (NMO, Devic's syndrome) following or coincidental with myasthenia gravis (MG). Their illnesses were characterized by subacute myelitis with optic neuritis, high serum levels of muscle acetylcholine receptor antibody, and autoimmune thyroid disease. Both patients fulfilled the clinical criteria of NMO, however, NMO-IgG, autoantibody against aquaporin-4 water channel, was absent from their sera. Both NMO and MG are relatively rare diseases. The considerable coincidence of these two disorders suggests that there is a subgroup of patients with NMO having a common immunological pathogenesis with MG.